cThis study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. S taphylococcus aureus and Streptococcus pneumoniae are the most common causes of hospital-acquired and communityacquired bacterial pneumonia, respectively (9, 10). Resistance to currently available antibiotics can be substantial, particularly for S. aureus, as methicillin resistance has been reported in upwards of 60% of S. aureus isolates (13). With respect to methicillin-resistant S. aureus (MRSA), few antibiotics are available to treat pneumonia caused by this organism. Vancomycin and linezolid are recommended as first-line therapy by recent guidelines (16). These agents are not without limitations, including nephrotoxicity and the requirement for therapeutic drug monitoring for vancomycin and myelosuppression for linezolid (29,32). Newer agents, including telavancin and ceftaroline, are not yet approved for MRSA pneumonia.Tedizolid phosphate free acid (TR-701 FA) is the prodrug of tedizolid (TR-700), an oxazolidinone active against many common respiratory Gram-positive bacteria, including methicillinsusceptible and -resistant S. aureus and S. pneumoniae (11,17,31). MICs for MRSA and pneumococcus are approximately 8-fold lower than those of linezolid (11). Because of this spectrum of activity and near-equivalent oral and intravenous (i.v.) bioavailability (2), tedizolid phosphate is being developed as i.v. and oral agents for the treatment of pneumonia. Murine pneumonia experiment results further support the development of this drug. Against S. pneumoniae, tedizolid achieved bacteriostatic and 1-log CFU killing at a dose 4.6-to 5.5-fold lower than the linezolid dose needed to achieve the same level of bacterial reductions (4). Another murine pharmacodynamic study demonstrated that ratios of the free area under the curve (fAUC) to MIC of 10 and 25 in plasma were required for bacteriostasis and a 1-log CFU killing against S. aureus isolates, respectively (22). These pharmacodynamic exposure targets were similar for linezolid and tedizolid.While murine infection model data provide insight into the possibility of tedizolid phosphate as a potential agent for the treatment of pulmonary infections, there are currently no data describing the extent of penetration into the site of infection. For pneumonia, the epithelial lining fluid (ELF) is presumed to be the site of infection for extrac...

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

cThis study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC 0 -12 ) for each respective parameter against free drug AUC (fAUC 0 -12 ) in plasma. The total AUC 0 -12 in plasma was 4.56 ؎ 0.94 g·h/ml with a mean fAUC 0 -12 of 0.77 ؎ 0.14 g·h/ml. T he world today is facing an emerging crisis of bacterial resistance in both community-and hospital-acquired pathogens. Extensive use of antibiotics, along with increased industrialization and international transit have all contributed to the rise in antimicrobial resistance, morbidity, and mortality (1-8). According to ATS/IDSA guidelines, the second most common nosocomial infection in the United States is hospital-acquired pneumonia representing 25% of all intensive care unit infections, an excess cost of $40,000 per patient, and an average increase in hospital stay of 7 to 9 days (8).Eravacycline (TP-434) is a novel fluorocycline antibiotic being developed as an intravenous (i.v.) and oral medication for the treatment of serious infections caused by antibiotic-resistant bacteria (9). In vitro microbiological studies of eravacycline have demonstrated potent, broad-spectrum Gram-positive and Gramnegative antibacterial effect exhibiting activity against S. aureus isolates expressing methicillin resistance, as well as Enterobacteriaceae isolates expressing resistance genes from multiple classes of extended-spectrum ␤-lactamase (ESBLs) (9). When tested against clinical isolates of A. baumannii, eravacycline displayed 2-fold greater susceptibility than tigecycline (9), whereas additional testing on Gram-positive isolates of Enterococcus displayed no difference in potency with or without the presence of vancomycin resistance (9). The results from a prospective, randomized, double-blind, phase II study evaluating the safety and efficacy of eravacycline dosed once or twice daily versus ertapenem given once daily in complicated intra-abdominal infections (cIAI) demonstrated Ͼ92% clinical cure rates at the test of cure visit, with 100% cure rates in the twice-daily dosing group with infections caused by ESBL-producing, levofloxacin-and ertapenem-resistant organisms (10).Although preclinical and clinical data offer insight into the use of eravacycline to treat bacterial infections, overall success is dependent upon optimizing drug exposures at the site of infection. We sou...

Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC 0-) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC 0-in plasma. The mean (standard deviation) half-life and AUC 0-were 6.9 (2.1) h and 39.5 (19.8) g ⅐ h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) g ⅐ h/ml, respectively, for anidulafungin. The AUC 0-values for ELF and AM were 282 and 178 g ⅐ h/ml, respectively, for voriconazole, and 21.9 and 1,430 g ⅐ h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC 90 /90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.

By way of bronchoscopy and bronchoalveolar lavage, intrapulmonary steady-state concentrations of micafungin administered at 150 mg daily to 15 healthy volunteers were determined at 4, 12, and 24 h after the third dose. The micafungin disposition was predominantly intracellular, with approximately 106% penetration into alveolar macrophages and 5% penetration into epithelial lining fluid.Invasive aspergillosis has drawn serious attention because of its high mortality and increasing prevalence within immunocompromised patients since the 1990s (13,19,20). Because most invasive aspergillosis infections occur in the respiratory tract (20), it is fundamentally important to provide adequate antifungal exposure to this difficult-to-reach infection site. As a result of the recent success of echinocandins combined with other first-line agents, the idea of combination therapy for invasive aspergillosis has been given serious consideration (16,21). Micafungin, a member of the echinocandin class, has potent in vitro activity against Aspergillus species and is considered an acceptable salvage therapy option for invasive pulmonary aspergillosis (4,22). While the pharmacokinetics of micafungin in plasma have been well described, the bronchopulmonary disposition is largely unknown, aside from data from animal studies (7). Bronchoscopy and bronchoalveolar lavage (BAL) studies with uninfected volunteers have become a useful approach for determining intrapulmonary pharmacokinetics for antimicrobials (3,5,6). To our knowledge, we describe the first investigation to determine the bronchopulmonary disposition of an echinocandin in healthy volunteers.This prospective phase I pharmacokinetic study was reviewed and approved by the Hartford Hospital investigational review board. The trial included 15 nonsmoking, healthy adults (20 to 46 years old) who met eligibility requirements based on a comprehensive medical evaluation and provided written informed consent prior to the study. Included participants received three 150-mg doses of micafungin (Astellas Pharma US, Inc., Deerfield, IL) administered intravenously over 1 h every 24 h.Blood samples were collected at 0 h (before the third dose), 1 h (at the end of the infusion of the third dose), and 4, 12, and 24 h after the third dose. As described previously, single bronchoscopy and BAL procedures for each participant were performed at either 4, 12, or 24 h after the third dose (five participants per time point) (3). After the initial aspirate was discarded, the remaining BAL aspirates were pooled (mean volume Ϯ standard deviation, 95 Ϯ 19 ml) and small portions were separated for complete cell count (mean value, 1.1 ϫ 10 7 cells/liter) and urea concentration determination. The remaining BAL fluid was centrifuged to separate the cell pellet. Urea concentrations in BAL fluid and plasma were analyzed with a colorimetric enzymatic assay (urea nitrogen diagnostic kit no. 640; Sigma, St. Louis, MO) by a detection method employing a spectrophotometer (Cary 50 series; Varian, Walnut Creek, CA). Mica...